1. Field of the Invention
This invention relates, generally, to a novel family of small molecule drugs. More particularly, it relates to selective estrogen receptor modulators for the prevention or treatment of estrogen receptor-mediated disorders.
2. Description of the Prior Art
Globally, breast cancer is the second most common cancer after lung cancer and the most common cancer for women following lung cancer. The breast cancer drug market is a steadily increasing market due to treatments which have decreased mortality and resulted in longer duration of therapy. The five-year survival rates for women with breast cancer have improved from under 70% about fifty years ago to around 90% now.
Approximately 47% of breast cancer drug sales were derived from the U.S., followed by 41% from Europe and 12% from Japan. Over the next six years the report forecasts that novel therapies, including targeted monoclonal antibodies and small-molecule inhibitors, will increasingly be used in combination with chemotherapy and hormonal therapy.
Estrogen is a hormone critical to normal human development and function. Although estrogen is the predominant “sex hormone” in women, in whom estrogen controls the development of female sex characteristics and the development and function of the reproductive system (Berkow, Beers et al. 1997), it is also found in men (Gustafsson 1998). Women produce estrogen primarily in the ovaries; however, estrogen affects a variety of physiological functions in women including body temperature regulation, maintenance of the vaginal lining, and preservation of bone density (Jordan 1998). In addition, estrogen provides additional effects that are related to its ability to modulate production of cholesterol in the liver, as demonstrated by the reduced occurrence of atherosclerosis in women compared to men due in part to the reduction of low-density lipoprotein (“LDL”) (Jordan 1998). Estrogen has also been implicated in delaying and/or reducing the severity of Alzheimer's Disease (Jordan 1998).
Failure to produce estrogen has profound physiological consequences in females. Failure to produce estrogen resulting from incomplete or absent ovary development (Turner's Syndrome) causes deficiencies in the skin, bone (e.g., severe osteoporosis), and other organs severely affecting the life of the afflicted individual (Dodge 1995). In normal women, estrogen production falls sharply upon the onset of menopause, usually at about 50 years of age. The effects of the loss of estrogen production include increased atherosclerotic deposits (leading to an increased incidence of heart disease), decreased bone density (osteoporosis), and fluctuations in body temperature (Jordan 1998). Often, the effects of reduced estrogen production are addressed by hormone replacement therapy (Dodge 1995; Berkow, Beers et al. 1997; Jordan 1998).
However, estrogen also has some undesirable side effects that may lead to estrogen receptor-mediated disorders. Though supplementation of estrogen in menopausal women is associated with alleviation of the above-described unwanted indications, administration of estrogen is also associated with increased risks for breast and endometrial cancer as well as blood clots (Jordan 1998). The increased risk of endometrial cancer can be addressed by the administration of progesterone (or its synthetic analog progestin) to re-initiate menstruation and thereby shed potentially malignant cells, but many older women find this undesirable (Jordan 1998). Breast cancer, however, is by far the greater risk of estrogen replacement therapy, affecting one woman in every fifteen women between the ages of 60 and 79 (Jordan 1998).
Certain selective estrogen receptor modulators (“SERMs”), for example tamoxifen, are known for regulating agonist and/or antagonist activities in estrogen receptors. Tamoxifen, U.S. Pat. Nos. 4,851,433 and 6,127,425, both of which are hereby incorporated by reference, is an antagonist of estrogen receptors in breast tissue but an agonist of estrogen receptors in endometrial tissue. Tamoxifen is often used as the endocrine therapy for hormone receptor-positive breast cancer (i.e., tamoxifen acts as an antagonist, or anti-estrogen) in pre-menopausal women. In post-menopausal women, tamoxifen is often used as well, but frequently in combination with aromatase inhibitors, which block the conversion of androgens into estrogen. Tamoxifen is metabolized into compounds that bind to estrogen receptors in breast tissue but do not activate the estrogen receptors. Thus, estrogen is blocked from binding to the estrogen receptors, hindering growth of breast cancer cells. However, tamoxifen can act on breast cancer cells for a limited amount of time, limiting its effectiveness.
Another existing SERM for the prevention and/or treatment of estrogen receptor-mediated disorders, such as breast cancer, in postmenopausal women can be found in U.S. Pat. No. 7,687,486 to Cooperwood, which is hereby incorporated by reference.
Accordingly, what is needed is a longer-lasting drug for estrogen receptor-mediated disorders, such as breast cancer, in postmenopausal women. However, in view of the art considered as a whole at the time the present invention was made, it was not obvious to those of ordinary skill how the art could be advanced.
While certain aspects of coventional technologies have been discussed to facilitate disclosure of the invention, Applicants in no way disclaim these technical aspects, and it is contemplated that the claimed invention may encompass one or more of the conventional technical aspects discussed herein.
The present invention may address one or more of the problems and deficiencies of the prior art discussed above. However, it is contemplated that the invention may prove useful in addressing other problems and deficiencies in a number of technical areas. Therefore, the claimed invention should not necessarily be construed as limited to addressing any of the particular problems or deficiencies discussed herein.
In this specification, where a document, act or item of knowledge is referred to or discussed, this reference or discussion is not an admission that the document, act or item of knowledge or any combination thereof was at the priority date, publicly available, known to the public, part of common general knowledge, or otherwise constitutes prior art under the applicable statutory provisions; or is known to be relevant to an attempt to solve any problem with which this specification is concerned.